Gonadal steroids are major neuroregulators and presumably underlie gender-related differences (sexual dimorphisms) in brain structure and function. We have studied reproductive endocrine-related mood disorders as well as developed endocrine models for these disorders in order to characterize the role of gonadal steroids in affective disturbance. Our major recent findings are as follows: 1) Demonstration that depression is induced by medroxyprogesterone but not placebo when added to estrogen in a subgroup of postmenopausal women. 2) Preliminary evidence of absence of the normal luteal phase decrease in central excitability in women with PMS (measured by paired pulse transcranial magnetic stimulation). 3) Demonstration of no differences between PMS patients (81) and controls (270) in the genotype or allele frequencies for the following polymorphisms: SLC6A4 promoter VNTR, 5HTR2C CYS23SER, 5HTR2A HIS452TYR, 5HTR2A T102C, ERalpha PVU II and Xba I. 4) Preliminary evidence of increased frequency of the serotonin receptor 2C CYS 23 SER polymorphism in women with a history of postpartum depression (n = 50), with no differences in the 5HT transporter or 5HT2A His/Tyr polymorphism. 5) Progesterone, but not estradiol, increases exercise stimulated cortisol (significantly) and ACTH (trend) secretion compared with an induced hypogonadal condition (n = 8). 6) Demonstration of sexual dimorphisms in the pituitary adrenal response to exercise: men have higher levels of ACTH during hypogonadal and replaced conditions, and gonadal state regulates the response in women but not in men. 7)Demonstration of differential susceptibility to gonadal steroid-related depressions in women with a history of premenstrual syndrome or postpartum depression compared with controls. These observations, then, demonstrate not only the marked impact of gonadal steroids on neuroendocrine function and behavior in humans, but demonstrate as well that women with histories of reproductive endocrine-related mood disorders display abnormal responses to normal levels of gonadal steroids.